Scientists have recently identified MMS22L as a potential major gene associated with prostate cancer (PCa) susceptibility, with implications for both risk prediction and personalised treatment, they say.
Building on existing knowledge that many genes linked to PCa, such as BRCA2, are involved in DNA repair and sensitivity to PARP inhibitor (PARPi) therapy, the researchers assessed 65 newly reported DNA repair-related genes for their association with PCa risk.
The investigation began with a comparison between 3 716 PCa patients from Johns Hopkins University and more than 103 000 population controls from the Genome Aggregation Database (gnomAD).
A significant finding emerged in men of Ashkenazi Jewish (ASJ) ancestry, where loss-of-function (LoF) mutations in MMS22L were more frequent among PCa patients than controls.
The European Medical Journal reports that the association was confirmed in additional patient cohorts and within the UK Biobank (UKB), strengthening the evidence base.
A particularly notable variant, F722fs, an ASJ founder mutation, showed a carrier rate of 1.5% in PCa cases versus 0.31% in controls. This translated to an odds ratio of 4.9, suggesting a strong association with increased PCa risk. Furthermore, 83% of mutation carriers had aggressive disease compared to just 27% of non-carriers.
Another founder mutation, c.340+1G>A, also demonstrated a significant association with PCa risk in the non-Finnish European population.
The study’s results – published in European Urology Focus – point to MMS22L as a novel gene with a role in PCa susceptibility, on par with the well-established BRCA2. Although these findings require validation and further analysis, especially regarding tumour DNA and response to PARPi therapy, they open up the possibility of incorporating MMS22L into risk stratification models.
If confirmed, this could help identify individuals at higher risk for aggressive disease and guide more targeted prevention and treatment strategies.
Study details
Discovery of a recurrent frameshift Ashkenazi Jewish founder mutation (F722fs) in the PARP inhibitor-sensitive MMS22L gene associated with higher risk of prostate cancer
William Isaacsa, Jun Weib, Marta Gielzak et al.
Published in European Urology Focus on 3 April 2025
Abstract
Background and objective
Most of the genes for which an association with susceptibility to prostate cancer (PCa) has been established (eg, BRCA2) are involved in DNA repair, with a subset involved in sensitivity to PARP inhibitor (PARPi) therapy. We systematically tested the association with PCa risk for 65 newly reported genes involved in these pathways.
Methods
Ancestry-specific association between loss-of-function (LoF) germline variants in these 65 genes and PCa risk was first tested between a cohort of PCa patients from Johns Hopkins University (Hopkins; n = 3,716) and population controls from the Genome Aggregation Database (gnomAD; n = 103,221). Results were confirmed in three additional PCa patient cohorts and the UK Biobank (UKB).
Key findings and limitations
Among men of Ashkenazi Jewish ancestry (ASJ), the carrier rate of LoF MMS22L mutations was significantly higher in the Hopkins PCa cohort than in the gnomAD control cohort. The association was confirmed in the UKB. Combined analysis of all cohorts revealed that the carrier rate for F722fs, an ASJ founder mutation, was 1.5% for PCa cases versus 0.31% for controls (odds ratio [OR] 4.9, 95% confidence interval [CI] 2.1–10.6; p = 1.44 × 10−4, Fisher’s test). The proportion of patients with aggressive disease was also significantly higher in the carrier group than in the non-carrier group (83% vs 27%; OR 12.3, 95% CI 2.2–132.5; p = 0.003, Firth test). Another founder mutation in the non-Finnish European population, c.340+1G>A, was significantly associated with PCa risk in the UKB (OR 7.7, 95% CI 2.6–21.0; p =5.10 × 10−4, Firth test). Somatic DNA analysis and assessment of the response to PARPi therapy are needed.
Conclusions and clinical implications
Our results suggest that MMS22L is a novel major gene associated with PCa susceptibility. Its carrier rate and effect size are similar to those for BRCA2. If these results are validated, MMS22L could be used for stratification of PCa risk and aggressiveness.
EMJ Reviews – New Prostate Cancer Risk Gene Identified (Creative Commons Licence)
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